Response to pioglitazone treatment is associated with the lipoprotein lipase S447X variant in subjects with type 2 diabetes mellitus

Wang, G.; Wang, X.; Zhang, Q.; Ma, Zhenzhen

doi:10.1111/j.1742-1241.2006.01242.x

Cited by 29 publications

(13 citation statements)

References 23 publications

(25 reference statements)

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“…These results are in agreement with those of Abd El-Haleim et al (36) and also indicate that treatment with TZD has a significant role on the serum lipid profile, as suggested by Wang et al (37). However, it has been previously reported that TZD administration may lead to deteriorating microvesicular steatosis and raised hepatic TG levels, through decreasing blood TG and free fatty acid (23).…”

Section: Discussionsupporting

confidence: 93%

Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl‑CoA desaturase‑1, lipase activity, leptin and resistin

Al‐Muzafar

Amin

2018

Exp Ther Med

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Hepatosteatosis is a disease present worldwide, which presents a number of health problems. Recently, thiazolidinedione (TZD) has been used as a therapy for lipid disorders. The present study demonstrates the potential of TZD as a treatment for hepatosteatosis and its mechanism of action, particularly focusing on its role in lipid metabolism. A total of 60 (80–90 g) rats were divided into three groups: A normal group with a standard diet, a high-fat, high-carbohydrate diet (HFCD) group or a HFCD+TZD group (n=20/group). The HFCD induced hepatosteatosis over a period of 12 weeks and the HFCD+TZD group were administered TZD in weeks 13–16. Blood and tissue samples were collected to measure hepatic function, the lipid profile, metabolism and hormone biomarkers, including serum triglyceride (TG), lipoprotein lipase (LPL), stearoyl-CoA desaturase (SCD-1), leptin and resistin. The HFCD-fed rats exhibited a significant increase in serum TG, total cholesterol, low-density lipoproteins, alanine transaminase and bilirubin compared with the normal group as well as a significant decrease in high-density lipoprotein. In addition, serum leptin and resistin were significantly elevated in the HFCD group compared with the normal group. The administration of TZD significantly increased SCD-1 activity and significantly inhibited LPL activity. It also attenuated the changes in the lipid profiles and normalized serum leptin and resistin levels. The results of the present study indicated that HFCD induced lipid abnormalities associated with hypertriglyceridemia, hypercholesterolemia and hepatosteatosis. These changes resulted from disruption to leptin and resistin, which may be due to alterations in LPL and SCD-1 activity. TZD mitigated the effects of HFCD-induced hepatosteatosis, indicating a possible regulatory effect of TZD in the development of hepatosteatosis. The authors suggest that the manipulation of SCD-1 and lipase by TZD may be useful as a treatment for hepatosteatosis.

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Section: Discussionsupporting

confidence: 93%

Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl‑CoA desaturase‑1, lipase activity, leptin and resistin

Al‐Muzafar

Amin

2018

Exp Ther Med

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“…Lipoprotein lipase is the rate-limiting enzyme for the breakdown of lipoproteins rich in triglycerides (Groenemeijer et al, 1997). Lipoprotein lipase is synthesized by and secreted from various parenchyma cells including adipocytes, muscle cells, and macrophages and expression was increased by PIO in a previous in vivo study (Bogacka et al, 2004; Wang et al, 2007). Among more than 40 polymorphisms in LPL gene, S447X is the most extensively studied polymorphism; it causes a premature stop codon and the elimination of serine and glycine at the C-terminal (Wang et al, 2007).…”

Section: Resultsmentioning

confidence: 83%

“…Lipoprotein lipase is synthesized by and secreted from various parenchyma cells including adipocytes, muscle cells, and macrophages and expression was increased by PIO in a previous in vivo study (Bogacka et al, 2004; Wang et al, 2007). Among more than 40 polymorphisms in LPL gene, S447X is the most extensively studied polymorphism; it causes a premature stop codon and the elimination of serine and glycine at the C-terminal (Wang et al, 2007). Previous independent studies reported an association of the S447X variant with dyslipoproteinemia and coronary artery disease (Kuivenhoven et al, 1997; Wang et al, 2007).…”

Section: Resultsmentioning

confidence: 83%

Current clinical evidence on pioglitazone pharmacogenomics

Kawaguchi‐Suzuki

Frye

2013

Front. Pharmacol.

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Pioglitazone is the most widely used thiazolidinedione and acts as an insulin-sensitizer through activation of the Peroxisome Proliferator-Activated Receptor-γ (PPARγ). Pioglitazone is approved for use in the management of type 2 diabetes mellitus (T2DM), but its use in other therapeutic areas is increasing due to pleiotropic effects. In this hypothesis article, the current clinical evidence on pioglitazone pharmacogenomics is summarized and related to variability in pioglitazone response. How genetic variation in the human genome affects the pharmacokinetics and pharmacodynamics of pioglitazone was examined. For pharmacodynamic effects, hypoglycemic and anti-atherosclerotic effects, risks of fracture or edema, and the increase in body mass index in response to pioglitazone based on genotype were examined. The genes CYP2C8 and PPARG are the most extensively studied to date and selected polymorphisms contribute to respective variability in pioglitazone pharmacokinetics and pharmacodynamics. We hypothesized that genetic variation in pioglitazone pathway genes contributes meaningfully to the clinically observed variability in drug response. To test the hypothesis that genetic variation in PPARG associates with variability in pioglitazone response, we conducted a meta-analysis to synthesize the currently available data on the PPARG p.Pro12Ala polymorphism. The results showed that PPARG 12Ala carriers had a more favorable change in fasting blood glucose from baseline as compared to patients with the wild-type Pro12Pro genotype (p = 0.018). Unfortunately, findings for many other genes lack replication in independent cohorts to confirm association; further studies are needed. Also, the biological functionality of these polymorphisms is unknown. Based on current evidence, we propose that pharmacogenomics may provide an important tool to individualize pioglitazone therapy and better optimize therapy in patients with T2DM or other conditions for which pioglitazone is being used.

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“…Polymorphism (S447X) in the LPL gene influences the beneficial effects of pioglitazone on cardiovascular complications of diabetes mellitus [80]. Such SNP mediates pioglitazone-linked increase in the synthesis and secretion of LPL in multiple types of parenchymal cells [81,82]. Studies have further shown that the S447X variant is intrinsically associated with the pathogenesis of dyslipoproteinemia and coronary artery disease and thus markedly reduces the efficacy of pioglitazone in the LPL S447X genotype when compared with subjects with the S447S genotype [82].…”

Section: Pharmacogenomics and Pharmacogenetics Of Pioglitazone In Diabetesmentioning

confidence: 99%

Pharmacogenomics and Pharmacogenetics of Thiazolidinediones: Role in Diabetes and Cardiovascular Risk Factors

et al. 2014

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The most important goal in the treatment of patients with diabetes is to prevent the risk of cardiovascular disease (CVD), the first cause of mortality in these subjects. Thiazolidinediones (TZDs), a class of antidiabetic drugs, act as insulin sensitizers increasing insulin-dependent glucose disposal and reducing hepatic glucose output. TZDs including pioglitazone, rosiglitazone and troglitazone, by activating PPAR-γ have shown pleiotropic effects in reducing vascular risk factors and atherosclerosis. However, troglitazone was removed from the market due to its hepatoxicity, and rosiglitazone and pioglitazone both have particular warnings due to being associated with heart diseases. Specific genetic variations in genes involved in the pathways regulated by TDZs have demonstrated to modify the variability in treatment with these drugs, especially in their side effects. Therefore, pharmacogenomics and pharmacogenetics are an important tool in further understand intersubject variability per se but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization.

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Response to pioglitazone treatment is associated with the lipoprotein lipase S447X variant in subjects with type 2 diabetes mellitus

Cited by 29 publications

References 23 publications

Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl‑CoA desaturase‑1, lipase activity, leptin and resistin

Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl‑CoA desaturase‑1, lipase activity, leptin and resistin

Current clinical evidence on pioglitazone pharmacogenomics

Pharmacogenomics and Pharmacogenetics of Thiazolidinediones: Role in Diabetes and Cardiovascular Risk Factors

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